The antibiotics of carbapenems represented by imipenem, meropenem, and biapenem, etc., have characteristics of broad-spectrum and super-strong antibacterial activity, β-lactamase stability and low toxicity, etc., which make them have become one of the most important antibacterial drugs for the treatment of severe bacterial infections.
Doripenem, with chemical name of (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl 7-oxo-3-[[(3S,5S)-5-[(aminosulfonylamino)-methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and structure shown in formula (I), is researched and developed by Japanese Shionogi & Co., Ltd, and came to market for the first time in Japan in 2005 under the trade name of “Finibax”, it belongs to antibiotics of 1-β methyl-type carbapenems, with broad-spectrum antibacterial activity. In recent years, various methods for preparing doripenem have been developed, in these methods, doripenem is usually prepared by reacting the parent nucleus compound (II) of carbapenem antibiotic compounds with the side-chain compound (III) of doripenem to obtain the intermediate compound (IV), and then removing the protecting group through catalytic hydrogenation, the reaction process is as follows:

According to the above reaction route, Organic Process Research & Development 2003, 7, 846-850 reported the following method for preparing doripenem (I):

In this method, the doubly-protected doripenem intermediate compound (VII) is prepared with yield of 88%, however, the intermediate compound (VII) is an amorphous foamy solid which is not easy to be purified and stored, while the purity of the intermediate compound (VII) has great impact on the subsequent step where de-protection is performed by catalytic hydrogenation (the yield of the subsequent step where doripenem (I) is obtained by removing protecting groups through catalytic hydrogenation is only 73%), therefore, this method is not a preferred method for industrial production of doripenem (I).
Patent EP0528678 reported a method for preparing doripenem by purifying the intermediate compound (VII) through column chromatography and then performing de-protection through catalytic hydrogenation. Although purification of the intermediate compound (VII) through column chromatography improves the yield of the subsequent step where the protecting groups are removed by catalytic hydrogenation (doripenem (I) can be obtained with yield of 84.8% by removing the protecting groups of the purified intermediate compound (VII) through catalytic hydrogenation), but the step of isolating and purifying the intermediate compound (VII) through column chromatography undoubtedly increases the production costs of doripenem and reduces the production efficiency, therefore, this method is also not a preferred method for industrial production of doripenem (I).
In order to overcome the difficulty in purification of the doubly-protected doripenem intermediate compound (VII), Patent CN101613351 reported a method for isolating and purifying the intermediate compound (VII). In this method, the methanol solvate crystal (VIII) of the doripenem intermediate compound (VII) is obtained from the doubly-protected doripenem intermediate compound (VII) under the specified condition (adding methanol successively into the solution of the intermediate compound (VII)):

Although the doubly-protected doripenem intermediate compound crystal (VIII) with a purity of above 98% can be obtained by this method at a certain yield (the maximum yield is 87%), which provides convenience for the purification of the intermediate compound (VII), this method needs a long operation time (it requires to stir for 8 hours to achieve yield of 87%), reducing the production efficiency, therefore, the method is still not a preferred method for industrial production of doripenem (I).
Patent WO2007009354 reported a method for preparing doripenem (I) by the route shown below:

In this method, a tri-protected doripenem intermediate compound (X) is firstly prepared, then doripenem (I) is prepared by de-protection reaction where catalytic hydrogenation is performed. Although this method avoids the step of removing protecting groups in the side-chain compound, this brings difficulties in the subsequent step where de-protection is performed by catalytic hydrogenation since the resulting intermediate compound (X) is an amorphous foamy solid which is not easy to be purified and stored; in addition, the intermediate compound (X) contains three protecting groups, increasing the complexity of de-protection by catalytic hydrogenation. The above two aspects result in low yield (49%) of the subsequent step where de-protection is performed by catalytic hydrogenation, therefore this method is not a preferred method for industrial production of doripenem (I).
In addition to the above three methods, Chinese Journal of Pharmaceuticals (2006, volume 37, No 6, Pages 361-363) also reported a method for preparing doripenem (I) by the route shown below:

In this method, as the protecting group of the side-chain compound (XI) is not consistent with that of the parent nucleus compound (II), the protecting groups of the doripenem intermediate compound (XII) are respectively removed with different methods in twice, which undoubtedly increases the reaction steps, reduces the use efficiency of the parent nucleus compound (II) and increases the production costs.
Further, since the doripenem intermediate compound (XIII) is directly subjected to de-protection by catalytic hydrogenation without purification, resulting in a low yield (58.1%) of the subsequent step where de-protection is performed by catalytic hydrogenation, therefore, this method is also not a preferred method for industrial production of doripenem (I).
Summarizing the above four methods, it can be seen that the protected doripenem intermediate compounds (such as intermediate compounds (VII), (X) and (XIII)) prepared by the existing preparation methods are not easy to be purified and stored, which brings many difficulties in the subsequent step where de-protection is performed by catalytic hydrogenation; additionally, the multiple protecting groups (such as intermediate compounds (VII) and (X)) also increase the complexity and difficulty in the subsequent step where de-protection is performed by catalytic hydrogenation, reduce the yield of the step where de-protection is performed by catalytic hydrogenation and increase the production costs, therefore, it is particularly important and urgent to find a protected doripenem intermediate compound which is easy to implement industrial production and purification and a more efficient method for de-protection by catalytic hydrogenation.